Reagent-Controlled Reversal of Regioselectivity in Nucleophilic Fluorination of Spiro-epoxyoxindole: Synthesis of 3-Fluoro-3-hydroxymethyloxindole and 3-Aryl-3-fluoromethyloxindole

Article abstract of DOI:10.1021/acs.joc.9b00059

A convenient and metal/catalyst-free approach for the reversal of regioselectivity in nucleophilic fluorination of a wide range of spiro-epoxyoxindoles has been reported simply by altering the nucleophilic fluoride reagents. Py·(HF)_x-mediated f

Full text of DOI:10.1021/acs.joc.9b00059

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Article
Reagent Controlled Reversal of Regioselectivity in Nucleophilic
Fluorination of Spiro-epoxyoxindole: Synthesis of 3-Fluoro-3-
hydroxymethyloxindole and 3-Aryl-3-fluoromethyloxindole
Saumen Hajra, Sayan Roy, Subrata Maity, and Sandip Chatterjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00059 • Publication Date (Web): 14 Jan 2019
Downloaded from http://pubs.acs.org on January 15, 2019
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Reagent Controlled Reversal of Regioselectivity in Nucleophilic
Fluorination of Spiro-epoxyoxindole: Synthesis of 3-Fluoro-3-
hydroxymethyloxindole and 3-Aryl-3-fluoromethyloxindole
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*
†
†
†§
†
Saumen Hajra, Sayan Roy, Subrata Maity and Sandip Chatterjee
†
§
Center of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus,
Raebareli Road, Lucknow 226014, India
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
Abstract
A convenient, as well as metal/catalyst-free approach for the reversal of regioselectivity in
nucleophilic fluorination of a wide range of spiro-epoxyoxindoles has been reported simply by
3
altering the nucleophilic fluoride reagents. Py·(HF) mediated fluorination at tertiary sp -C-
x
center of spiro-epoxyoxindole furnishes 3-fluoro-3-hydroxymethyl oxindoles whereas TBAF
3
mediated fluoride addition at primary sp -C-center renders 3-fluoromethyl-3-hydroxy
oxindoles, which have been utilized for the synthesis of 3-aryl-3-fluoromethyl oxindole.
Ar
F
HO
O
ArH
F
OH
F
Lewis acid (cat)
TBAF
Py.(HF)x
O
O
O
O
N
N
N
N
PG
PG
PG
C-3 fluoromethylation
5 examples
PG
3
1
2
Fluoromethyl containing
all carbon quarternary centre
C-3 fluorination
6 examples
1
1
Introduction
The presence of a fluorine atom in an organic molecule has an immense impact on their
physico-chemical as well as biological properties; thus transforming these molecules to
1
potentially more promising scaffolds than those of the nonfluorinated analogues. Because of
the ubiquity of the fluorinated compounds in pharmaceutical, agrochemical and radio-
chemicals, methods for the incorporation of a fluorine atom in an organic molecule are
2
tremendously demanding. However, the inclusion of a single fluorine atom does not alter the
steric factor of the molecule; rather it refines the electronic factors, which are especially
important for the proper tuning of biological activity. Since, the 3,3-disubstituted oxindole ring
is a prevalent motif in numerous natural products and drug molecules, its fluorinated analogues
may enhance the pharmaceutical efficacy and medicinal potency. For example, MaxiPost (A)
developed by Bristol-Myers Squibb is a promising potassium channel opener for the treatment
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of stroke, whereas compound B is reported to be a corticotropin-releasing factor receptor
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antagonist for the treatment of anxiety and compound C is an antipsychotic drug candidate
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(
Figure 1). On the otherhand, introduction of a fluoromethyl unit to the C-3 position of
oxindole may unveil amazingly potential bioactivity since -CH F is the isosteric
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correspondence to a –CH group.
3
O
MeO
F
NHMe
O
F
Cl
N
O
N
F3C
H
A
Maxipost
C
F
Me
R1
CH2F
R2
O
Me
N
O
N
D
B
NH
Fluoromethyl containing all
carbon quaternary centre
Cl
Figure 1. Representative fluorine containing oxindole compounds.
These fascinating properties of the fluorinated oxindoles lure the synthetic fraternity to develop
efficient methods to introduce the fluorine atom to oxindoles. One conventional approach of
C-F bond formation is electrophilic fluorination of 3-substituted oxindole employing proper
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electrophilic fluorinating agents (Scheme 1, eq 1). Another synthetic route implicating the C-
C bond forming reaction of pre-installed 3-fluorooxindole was delineated in recent time
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(
Scheme 1, eq 1). Despite of the progress in this area, nucleophilic fluorination is more
advantageous due to the low cost of the fluoride reagent as well as the substrate. Moreover, the
paramount significance of the fluorine chemistry is PET (Positron Emmision Tomography), a
nuclear medicine functional imaging technique to recognize the progress of disease and to
1
8 -
evaluate therapeutic efficacy. To prepare the radioactive tracers, nucleophilic fluoride ( F ) is
the most desirable as well as readily available source due to its high specific activity. Hence
nucleophilic fluorination is more effective than electrophilic methods regarding the application
in PET. To the best of our knowledge, there is hardly any report of nucleophilic fluorination at
sterically congested C-3-carbon centre of oxindole.9d Besides these, incorporation of a
monofluoromethyl group to C-3 position of oxindole is still a formidable challenge;6d
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specifically the synthesis of fluoromethyl containg all carbon quaternary center is infrequent
in the literature. Even though such difficulties, diverse as well as pioneering work in this field
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suggested that epoxides and aziridines are familiar substrates for nucleophilic fluorination.2a,
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c, 9b, 10
Moved by the challenges and inspired by these reports and our recent outcome on ring
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1
opening reactions of spiro-compounds, we envisaged that spiro-epoxyoxindole can provide
both the functionality by proper tuning of fluorinating reagent and the reaction conditions.
Herein, we successfully narrate the reagent dependent reversal of regioselectivity in
nucleophilic fluorination of spiro-epoxyoxindole which inturn bestows 3-fluoro-3-substituted
oxindole as well as 3-fluoromethyl-3-substituted oxindole concurrently (Scheme 1, eq 2).
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Scheme 1. Previous reports and the present work
Previous works
Electrophilic fluorination and C-C bond-forming reaction for the synthesis of 3-fluoro-3-
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, 8
substituted oxindoles
R
F
R
H
H
F
F+ source
carbon electrophile
O
N
O
(1)
O
N
N
PG
PG
PG
Our work
Reversal of regioselectivity in nucleophilic fluorination of spiro-epoxyoxindole
F
HO
O
OH
F
TBAF
Py (HF)x
·
O
O
O
(2)
N
N
N
3
PG
PG
C-3 fluoromethylation
1
PG
2
C-3 fluorination
Proposed Reactivity Pattern of Spiro-epoxyoxindole
If we deeply look into the reactivity pattern of the spiro-epoxide, it can easily protonate under
acidic condition and formed the protonated structure 1′ (Scheme 2).11h This protonated
structure can be opened up via S 1 fashion to form the benzylic carbocationic intermediate 4a
N
or its canonical form 2H-indol-2-one intermediate 4b. At that moment, fluoride ion can add to
the C-3 center of the reactive intermediate 4 to form 3-fluoro-3-hydroxymethyloxindole 2
12
(
Scheme 2, path a). Alternatively, in the absence of any acid, fluoride ion can directly add to
3
the primary sp -C center of epoxide 1 via S 2 mechanism to furnish 3-fluoromethyl-3-
N
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hydroxyoxindole 3 (Scheme 2, path b). Therefore, nucleophilic fluorinating reagents along
with solvent may play a crucial role in defining the regioselectivity.2g
Scheme 2. Proposed reactivity pattern of spiro-epoxyoxindole for nucleophilic
fluorination reaction
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a
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OH
O
H
HF
O
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path a
N
N
N
R
N
SN1
R
R
R
4a
4b
H-indol-2-one
1
1'
2
path b MF
O
b
F
HO
F
F
OH
S 2
N
O
O
O
N
N
N
1''
R
3
R
2
R
Results and Discussion
To gain a proof of concept, we embarked on a research endeavour by exploiting different
nucleophilic fluorinating agents on our candidate substrate N-methyl spiro-epoxyoxindole 1a.
To the onset, when the most familiar acidic nucleophilic fluorinating agent, Py·(HF) (Olah’s
x
reagent) was applied in DCE at rt, desired 3-fluoro-3-hydroxymethyl oxindole 2a was solely
1
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achieved in 55% isolated yield within 2 h, which was confirmed by the crude F NMR (Table
, entry 1). Lowering the temperature to 0 °C retarded the reaction with a trace yield. However,
changing the solvent to CH Cl , eventually increased the yield up to 70% within 1.5 h at rt
1
2
2
(
Table 1, entry 3). While the fluorination reaction in CHCl produced comparable yield,
3
reactions in THF, ether, dioxane, MeCN or DMF were sluggish and mostly afforded low yields
with incomplete conversions (Table 1, entries 4-9). We further applied other acidic fluorinating
agents like Et N·3HF, but it did not exhibit promising result than Py·(HF) (Table 1, entry 10).
3
x
To expose the fluoride ion for the S 2 reaction, when we investigated the fluorination reaction
N
by applying other metal fluorides like KF, CsF or NaF in polar aprotic DMF solvent, initially
we were disheartened not to afford any product with the full recovery of starting material (Table
1
, entries 11-13). Eventually we were delighted to isolate 38% of the desired opposite
regioisomer 3-fluoromethyl-3-hydroxyoxindole 3a when we employed tetrabutylammonium
fluoride (TBAF, 1M solution in THF) in DMF at rt which was also confirmed by the crude 19F
NMR (Table 1, entry 14). We also obtained 3a with 30% isolated yield with TBAF in CH Cl
2
2
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at rt. Varying the solvent to DCE, THF or MeCN did not improve the yield. (Table 1, entries
15-18). Finally, increasing the temperature to 50 °C in DMF, we were pleased to isolate 63%
Table 1. Optimization of reaction conditionsa
F
O
HO
1
1
1
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0
OH
F
F- source
O
O
O
+
solvent, temp, t
N
N
N
Me
Me
Me
3a
2a
1a
b
entry fluoride
source
solvent temp t
yield (%)
(°C) (h) 2a
3a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
Py·(HF)x
Py·(HF)x
Py·(HF)x
Py·(HF)x
Py·(HF)x
Py·(HF)x
Py·(HF)x
Py·(HF)x
Py·(HF)x
DCE
DCE
25
0
2
6
55
-
trace -
CH Cl 25
1.5 70
-
-
-
-
2
2
CHCl3
25
25
25
2
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
12
6
6
50
12
10
THF
Et O
2
dioxane 25
trace -
15
trace -
MeCN
DMF
25
25
25
25
25
25
25
25
25
25
25
50
80
-
0
1
2
3
4
5
Et N·3HF CH Cl
15
-
-
3
2
2
KF
DMF
-
CsF
DMF
DMF
DMF
-
-
NaF
-
-
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
-
38
30
22
25
CH Cl
-
2
2
16
DCE
THF
-
1
7
-
18
MeCN
DMF
DMF
-
trace
63
1
9
-
20
-
58
2
1
DMSO 25
DMSO 50
-
60
22
-
messy
42
2
3
CH Cl
50
-
2
2
a
N-methyl spiro-epoxyoxindole 1a (0.285 mmol), fluoride reagent (3 equiv) in 2 mL solvent was stirred at
b
specified temperature. Isolated yield. TBAF: 1M solution in THF
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of 3-fluoromethyl-3-hydroxyoxindole 3a within 6 h (Table 1, entry 19). Further hike of
temperature did not boost the yield or decrease the reaction time. Reaction in DMSO at rt
imparted comparable yield although it required longer reaction time for full conversion (Table
1
, entry 21). Other attempts mostly rendered lower yield with incomplete conversion as well
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as unclean reaction (Table 1, entries 22-23). Thus acidic Olah’s reagent in CH Cl at rt was
2
2
manifested to be the superior condition for C-3 fluorination; whereas the C-3 fluoromethylation
was obtained in polar aprotic solvent DMF utilizing TBAF at 50 °C which also supported our
presumption.
Substrate Scope for C-3 Fluorination Reaction
We instigated to explore the generality of the fluorination reactions with the armoury of the
optimized studies. At first, we executed the C-3 fluorination reaction, which was conveniently
applied to a wide range of spiro-epoxides (Figure 2). All the N-methyl, N-benzyl, N-allyl and
N-phenyl spiro-epoxides underwent smooth reaction while employing Olah’s reagent in
CH Cl and afforded the desired 3-fluoro-3-hydroxymethyl oxindoles 2 with good to excellent
2
2
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F
F
F
OH
O
OH
O
OH
O
N
N
N
Allyl
Me
Bn
2
a (1.5 h, 70%)
2b (2 h, 79%)
2c (2 h, 73%)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
2
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0
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0
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0
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0
1
2
3
4
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9
0
F
F
F
Me
OH
O
Cl
OH
O
OH
O
N
N
N
Me
Me
Ph
2
d (2 h, 74%)
2e (1.5 h, 72%)
2f (2.5 h, 71%)
F
F
F
I
OH
O
OH
Br
OH
O
O
N
Me
N
Me
N
Me
Cl
2
g (2 h, 66%)
2h (2 h, 58%)
2i (2 h, 68%)
F
F
F
MeO
OH Cl
O
OH
Br
OH
O
N
Bn
O
N
N
Bn
Bn
2
j (2 h, 69%)
2k (3 h, 76%)
2l (3 h, 82%)
F
F
F
F
F
OH I
O
OH
OH
O
OH
O
O
N
N
N
N
H
Bn
m (3 h, 77%)
Bn
Ts
2o (1 h, 62%) 2p (2 h, 66%)
2
2n (3 h, 79%)
Figure 2. Substrate scope for C-3 fluorination reaction.
yields. Subsequently, substituted spiro-epoxyoxindoles also participated in this transformation
with good yields. Electron donating as well as electron withdrawing groups on the oxindole
ring did not interrupt in the nucleophilic fluorination reactions; even if the electron deficient
substituents required a little longer reaction time for completion. Even the unprotected spiro-
epoxyxoxindole imparted good yield of 2o under the optimized conditions. Finally, we
performed the C-3 fluorination reaction of the spiro-epoxide bearing an electron withdrawing
group on nitrogen atom. Under the optimised conditions, it also offered the desired 3-fluoro-3-
hydroxymethyl oxindole 2p with good yield within 2 h.
Substrate Scope for C-3 Fluoromethylation Reaction
Afterwards efforts were invested in exploring the scope and limitation of the synthesis of
opposite regio-isomer, i.e. C-3 fluoromethylation reaction utilizing TBAF in DMF (Figure 3).
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Irrespective of the N-protection on spiro-epoxide, we acquired 3-fluoromethyl-3-
hydroxyoxindoles 3 with moderate to good yields in all the cases. In striking contrast,
unprotected spiro-epoxyxoxindole did not undergo fluoromethylation reaction. This might be
due to the fact that the fluoride anion immediately quenched by the –NH proton of unprotected
spiro-epoxyoxindole; thus lost its nucleophilicity along with the elctrophilicity of the
deprotonated epoxide. Although substituted spiro-epoxyoxindoles experienced smooth
reaction and furnished corresponding 3-fluoromethyl -3-hydroxy oxindoles 3 with good yields.
However, electron withdrawing protecting group on the N-atom of spiro-epoxide impeded the
fluorination reaction.
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3
4
5
6
7
8
9
0
HO
HO
HO
F
F
F
O
O
O
N
N
N
Allyl
Me
Bn
3a (6 h, 63%)
3b (8 h, 59%)
3c (6 h, 66%)
HO
HO
HO
Me
F
F Me
F
O
O
O
N
Me
N
N
Me
PMB
Me
3d (8 h, 70%)
3e (6 h, 65%)
3f (6 h, 66%)
HO
HO
HO
F
Cl
F
I
F
O
O
O
N
Me
N
Me
N
Me
Cl
3g (8 h, 59%)
3h (7 h, 62%)
3i (8 h, 60%)
HO
HO
HO
Me
F
Br
F F
F
O
O
O
N
N
N
Bn
Me
Bn
Bn
3j (8 h, 55%)
3k (10 h, 58%)
3l (12 h, 57%)
HO
F
HO
F
HO
F
I
O
N
Bn
O
O
N
N
H
Ts
3
m (10 h, 58%)
3n (12 h, N.R.)
3o (12 h, N.R.)
Figure 3. Substrate scope for C-3 fluoromethylation reaction; N.R. = No Reaction.
Application of the Methodology
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Next, we elaborated our work towards the synthetic potential and effectiveness of the method.
In this process, to show the general utility of the methodology, both the fluorination reactions
were performed on gram scale; albeit a little erosion of yield in both the cases. To demonstrate
the application, we subjected both the fluorinated compounds (2b and 3a) to a variety of
transformations (Scheme 3 and 4). An initial effort was devoted towards the Appel reaction of
3-fluoro-3-hydroxymethyl oxindole 2b which furnished the corresponding bromide 5 in a
quantitative yield. Later we were pleased to convert 2b to corresponding tosylate 6 by
tosylation of the primary hydroxyl group of 3-fluoro-3-hydroxymethyl oxindole. Subsequent
treatment of the tosylate 6 with sodium azide bestowed the β-fluoroazide 7 with excellent yield.
Furthermore, to synthesize the compound B like structure (Figure 1), we treated the tosylate 6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with super hydride, LiEt BH; but it only manifested 3-methyl oxindole 8 in excellent yield.
3
Here super hydride not only removed –OTs group but also displaced fluoride by hydride via
1
3
hydrodefluorination (HDF) reaction to furnish compound 8 (Scheme 3).
Scheme 3. Gram scale C-3-fluorination reaction and selective transformations
O
F
F
Py·(HF)x
CH Cl , rt
OH
Br
PPh , CBr
3
4
O
O
O
N
b Bn
N
2
2
DCE, 50 °C
95%
N
1
Bn
72%
2b
5
Bn
[1 g scale]
Et N, DMAP(cat.)
3
95%
TsCl, CH Cl , rt
2
2
OTs
H
F
F
LiEt BH, THF
Me
3
N3
NaN , DMF
3
0 °C to 25 °C
O
O
O
95%
N
N
100 °C, 90%
N
HDF reaction
Bn
Bn
Bn
8
7
6
Since, construction of fluoromethyl containing all carbon quaternary center is really
challenging, as an appended application, 3-fluoromethyl-3-hydroxyoxindole 3a was initially
converted to trichloroacitimidate 9 with trichloroacetonitrile in the presence of DBU.
Subsequent Lewis acid catalyzed addition of nucleophile to the corresponding imidate rendered
the 3,3′-disubstituted oxindoles. BF .OEt was found to be the superior catalyst for anisole
3
2
rendering compound 10 in excellent yield (Scheme 4).
Scheme 4. Gram scale C-3-fluoromethylation reaction and synthesis of 3-aryl-3-
fluoromethyl oxindoles
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5
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HN
F
O
HO
DBU
CCl3
O
TBAF
CCl CN
3
F
O
O
CH Cl2
2
O
N
a Me
DMF, 50 °C
N
0 °C to 25 °C
N
Me
1
3a Me
60%
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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7
8
9
0
1
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9
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8
9
0
1
2
3
4
5
6
7
8
9
0
[1 g scale]
9
anisole
9
0% BF -OEt (cat)
3
2
DCE, rt
OMe
F
O
N
Me
1
0
Conclusion
In conclusion, an efficient as well as inexpensive strategy for the reagent dependent reversal of
regioselectivity in nucleophilic fluorination of a range of spiro-epoxyoxindoles has been
reported. This method thus furnishes 3-fluoro-3-hydroxymethyloxindole as well as 3-
fluoromethyl-3-hydroxyoxindole through fine-tuning of reaction conditions. The gram-scale
reactions followed by further transformations prove its applicability. This method is also found
to be worthy for the synthesis of fluoromethyl containing all carbon quaternary center. Hence,
we believe that the present development paves a new way for the nucleophilic fluorination
chemistry and unfolds a new avenue in fluorine containing oxindole based drug discovery as
well as medicinal chemistry research.
Experimental Section
General Information: All the reactions were carried out using oven dried glassware under an
atmosphere of argon (Ar). All reagents were used as purchased from commercial supplier
without further purification. Solvents were dried and distilled following usual protocols.
Heating reactions were performed in silicon oil bath at the specified temperature. Flash column
chromatography was performed in all cases using the indicated solvent system on silica gel
(
230-400 mesh) purchased. Analytical thin layer chromatography was performed using 60
F254 precoated silica gel plate (0.2 mm thickness) and compounds were visualized by
1
13
19
irradiation of UV light. The H NMR, C NMR and F NMR spectra were measured with 400
400 MHz) using CDCl and DMSO-d . Electro spray ionization (ESI) mass spectrometry (MS)
(
3
6
experiments were performed on Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS.
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Melting points were measured with a Stuart SMP30 apparatus and are uncorrected. Spiro-
epoxides 1 were prepared by common literature procedures.11a,b
General procedure for ring-opening reaction spiro-epoxyoxindoles with Py·(HF) : To a
x
stirring solution of spiro-epoxy oxindole 1a (0.100 g, 0.570 mmol) in a teflon vial in dry
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
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5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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8
9
0
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7
8
9
0
dichloromethane (4 mL) at 25 °C, Py·(HF) (0.154 g, 1.712 mmol) was added. The resulting
x
solution was stirred at the same temperature and monitored by TLC. On completion (1 h), the
reaction mixture was concentrated and purified by silicagel flash chromatography using
EtOAc/hexane (2:3) to afford the desire product 2a (0.076 g, 68%).
3
-Fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (2a): The compound was prepared by
1
following general procedure and was obtained as gummy liquid (0.082 g, 70%). H NMR (400
MHz, CDCl ) δ 7.52 (dt, J = 7.4, 1.3 Hz, 1H), 7.44 (tt, J = 7.8, 1.5 Hz, 1H), 7.15 (t, J = 7.6 Hz,
3
1
3
1
1
H), 6.89 (d, J = 7.8 Hz, 1H), 4.16 – 4.02 (m, 2H), 3.23 (s, 3H), 2.42 (br. s, 1H). C{ H} NMR
100 MHz, CDCl ) δ 171.8 (d, J = 21 Hz), 144.3 (d, JC-F = 5 Hz), 131.60 (d, JC-F = 3 Hz),
(
3
C-F
1
25.3, 123.9 (d, JC-F = 19 Hz), 123.4 (d, JC-F = 2 Hz), 108.9, 91.5 (d, JC-F = 189 Hz), 64.4 (d,
1
9
+
JC-F = 30 Hz), 26.3. FNMR (CDCl , 376 MHz): δ -169.5. HRMS (ESI-TOF) m/z: [M+Na]
3
Calcd for C H FNO Na 218.0588; found 218.0563.
10
10
2
1-Benzyl-3-fluoro-3-(hydroxymethyl)indolin-2-one (2b): The compound was prepared by
following general procedure and was obtained as white solid (0.087 g, 79%), mp 128−130 °C.
1
H NMR (400 MHz, CDCl ) δ 7.56 – 7.49 (m, 1H), 7.38 – 7.24 (m, 6H), 7.11 (t, J = 7.6 Hz,
3
1
H), 6.75 (d, J = 7.9 Hz, 1H), 4.98 (d, J = 15.7 Hz, 1H), 4.85 (d, J = 15.7 Hz, 1H), 4.16 (dd, J
1
3
1
= 16.3, 4.6 Hz, 2H), 2.38 (br. s, 1H). C{ H} NMR (100 MHz, CDCl ) δ 171.9 (d, J = 21
3
C-F
Hz), 143.5 (d, JC-F = 5 Hz), 134.8, 131.5 (d, JC-F = 3 Hz), 128.9, 127.9, 127.1, 125.34, 124.0
(d, JC-F = 19 Hz), 123.4 (d, JC-F = 2 Hz), 109.94, 91.5 (d, JC-F = 189 Hz), 64.5 (d, JC-F = 31 Hz),
1
9
+
4
3.8. F NMR (CDCl , 376 MHz): δ -169.1. HRMS (ESI-TOF) m/z: [M+Na] Calcd for
3
C H FNO Na 294.0901; found 294.0875.
1
6
14
2
1
-Allyl-3-fluoro-3-(hydroxymethyl)indolin-2-one (2c): The compound was prepared by
1
following general procedure and was obtained as yellow gummy liquid (0.080 g, 73%). H
NMR (400 MHz, CDCl ) δ 7.52 (dt, J = 7.4, 1.6 Hz, 1H), 7.40 (tt, J = 7.8, 1.6 Hz, 1H), 7.18 –
3
7
2
.08 (m, 1H), 6.88 (d, J = 7.9 Hz, 1H), 5.84 (ddt, J = 17.3, 10.3, 5.2 Hz, 1H), 5.31 – 5.21 (m,
H), 4.34 (qdt, J = 16.4, 5.2, 1.6 Hz, 2H), 4.05 – 4.17 (m, 2H) (dd, J = 16.9, 5.0 Hz, 2H), 2.34
1
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5
5
5
5
5
5
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1
(
br. s, 1H). C{ H} NMR (100 MHz, CDCl ): δ 171.6 (d, J = 21 Hz), 143.5 (d, JC-F = 5 Hz),
3 C-F
131.5 (d, JC-F = 3 Hz), 130.5, 125.4, 123.9 (d, JC-F = 18 Hz), 123.4 (d, JC-F = 2 Hz), 118.1,
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9
1
1
09.8, 91.5 (d, JC-F = 189 Hz), 64.4 (d, JC-F = 31 Hz), 42.3. F NMR (CDCl , 376 MHz): δ -
3
+
69.4. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H FNO Na244.0744; found 244.0727.
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2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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3
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7
8
9
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3-Fluoro-3-(hydroxymethyl)-1-phenylindolin-2-one (2d): The compound was prepared by
1
following general procedure and was obtained as yellow gummy liquid (0.077 g, 74%). H
NMR (400 MHz, CDCl ) δ 7.63 – 7.50 (m, 3H), 7.50 – 7.40 (m, 3H), 7.37 (tt, J = 7.8, 1.6 Hz,
3
1
H), 7.19 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.28 – 4.12 (m, 2H), 2.41 (dd, J = 7.0,
1
3
1
4.4 Hz, 1H). C{ H} NMR (100 MHz, CDCl ) δ 171.1 (d, J = 21 Hz), 144.4 (d, JC-F = 4
3
C-F
Hz), 133.3, 131.5 (d, JC-F = 3 Hz), 129.8, 128.6, 126.3, 125.6, 123.9 (d, JC-F = 3 Hz), 123.7,
19
1
10.2, 91.6 (d, JC-F = 189 Hz), 64.6 (d, JC-F = 30 Hz). F NMR (CDCl , 376 MHz): δ -168.1.
3
+
HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H FNO Na 280.0744; found 280.0727.
1
5
12
2
3
-Fluoro-3-(hydroxymethyl)-1,5-dimethylindolin-2-one (2e): The compound was prepared
by following general procedure and was obtained as white solid (0.080 g, 72%), mp 120−122
1
°C. H NMR (400 MHz, CDCl ) δ 7.33 (br. s, 1H), 7.23 (dtt, J = 8.0, 1.8, 0.8 Hz, 1H), 6.77
3
(
dd, J = 8.0, 1.2 Hz, 1H), 4.01 - 4.13 (m, 2H), 3.20 (s, 3H), 2.49 (br. s, 1H), 2.36 (s, 3H).
13
1
C{ H} NMR (100 MHz, CDCl ) δ 171.7 (d, J = 21 Hz), 141.8 (d, JC-F = 5 Hz), 133.2 (d,
3
C-F
JC-F = 2 Hz), 131.7 (d, JC-F = 3 Hz), 126.0, 123.9 (d, JC-F = 19 Hz), 108.6, 91.6 (d, JC-F = 189
1
9
Hz), 64.4 (d, JC-F = 30 Hz), 26.3, 21.0. F NMR (CDCl , 376 MHz): δ -169.5. HRMS (ESI-
3
+
TOF) m/z: [M+Na] Calcd for C H FNO Na 232.0744; found 232.0731.
1
1
12
2
5-Chloro-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (2f): The compound was
prepared by following general procedure and was obtained as yellow solid (0.079 g, 71%), mp
1
1
03−105 °C. H NMR (400 MHz, CDCl ) δ 7.53 (t, J = 2.0 Hz, 1H), 7.41 (dt, J = 8.3, 1.9 Hz,
3
1
H), 6.82 (dd, J = 8.3, 1.3 Hz, 1H), 4.14 (dd, J = 14.9, 12.4 Hz, 1H), 4.07 – 3.92 (m, 1H), 3.21
1
3
1
(s, 3H), 2.41 (br. s, 1H). C{ H} NMR (100 MHz, CDCl ) δ 171.3 (d, J = 20 Hz), 142.7 (d,
3
C-F
JC-F = 5 Hz), 131.3 (d, JC-F = 3 Hz), 128.9 (d, JC-F = 3 Hz), 126.1, 125.6 (d, JC-F = 18 Hz), 109.8,
19
9
1.5 (d, JC-F = 190 Hz), 64.1 (d, JC-F = 31 Hz), 26.4. F NMR (CDCl , 376 MHz): δ -169.7.
3
+
HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H ClFNO Na 252.0198; found 252.0180.
1
0
9
2
3
-Fluoro-3-(hydroxymethyl)-5-iodo-1-methylindolin-2-one (2g): The compound was
prepared by following general procedure and was obtained as white solid (0.068 g, 66%), mp
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28−130 °C. H NMR (400 MHz, CDCl ) δ 7.82 (t, J = 1.8 Hz, 1H), 7.74 (dt, J = 8.2, 1.8 Hz,
3
1H), 6.67 (dd, J = 8.2, 1.3 Hz, 1H), 4.12 (dd, J = 14.6, 12.4 Hz, 1H), 3.99 (dd, J = 19.1, 12.3
1
3
1
Hz, 1H), 3.19 (s, 3H), 2.54 (br. s, 1H). C{ H} NMR (100 MHz, CDCl ) δ 171.0 (d, J = 20
3
C-F
Hz), 143.9 (d, JC-F = 5 Hz), 140.2 (d, JC-F = 3 Hz), 134.2, 126.2 (d, JC-F = 18 Hz), 110.8, 91.2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
19
(
d, JC-F = 190 Hz), 85.7 (d, JC-F = 3 Hz), 64.1 (d, JC-F = 30 Hz), 26.3. F NMR (CDCl , 376
3
+
MHz): δ -169.7. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H FINO Na343.9554; found
1
0
9
2
3
43.9539.
5
-Bromo-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (2h): The compound was
prepared by following general procedure and was obtained as white solid (0.063 g, 58%), mp
1
1
28−129 °C. H NMR (400 MHz, CDCl ): δ 7.77 – 7.61 (m, 1H), 7.64 – 7.46 (m, 1H), 6.77
3
(
d, J = 8.4 Hz, 1H), 4.14 (t, J = 13.6 Hz, 1H), 4.01 (dd, J = 19.3, 12.4 Hz, 1H), 3.21 (s, 3H),
1
3
1
2.36 (br. s, 1H). C{ H} NMR (100 MHz, CDCl ): δ 171.1 (d, J = 20.5 Hz), 143.3 (d, JC-F
3
C-F
=
5.0 Hz), 134.3 (d, JC-F = 2.8 Hz), 128.8, 125.9 (d, JC-F = 18.5 Hz), 116.1 (d, JC-F = 2.9 Hz),
1
9
1
10.3, 91.3 (d, JC-F = 190.0 Hz), 64.2 (d, JC-F = 30.1 Hz), 26.4. F NMR (CDCl , 376 MHz):
3
+
δ -169.6. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H BrFNO Na 295.9693; found
1
0
9
2
295.9674.
7
-Chloro-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (2i): The compound was
prepared by following general procedure and was obtained as gummy liquid (0.073 g, 68%).
1
H NMR (400 MHz, CDCl ) δ 7.42 (ddd, J = 7.3, 2.1, 1.2 Hz, 1H), 7.36 (dt, J = 8.3, 1.4 Hz,
3
1
H), 7.06 (ddd, J = 8.2, 7.3, 0.9 Hz, 1H), 4.15 – 3.99 (m, 2H), 3.59 (s, 3H), 2.29 (br. s, 1H).
13
1
C{ H} NMR (100 MHz, CDCl ) δ 172.0 (d, J = 20 Hz), 140.1 (d, JC-F = 5 Hz), 133.8 (d,
3
C-F
JC-F = 3 Hz), 126.7 (d, JC-F = 18 Hz), 124.3 (d, JC-F = 2.6 Hz), 123.9, 116.4, 90.7 (d, JC-F = 188
1
9
Hz), 64.4 (d, JC-F = 30 Hz), 29.7. F NMR (CDCl , 376 MHz): δ -168.5. HRMS (ESI-TOF)
3
+
m/z: [M+Na] Calcd for C H ClFNO Na 252.0198; found 252.0182.
1
0
9
2
1-Benzyl-3-fluoro-3-(hydroxymethyl)-5-methoxyindolin-2-one (2j): The compound was
prepared by following general procedure and was obtained as brown solid (0.073 g, 69%), mp
1
1
48−149 °C. H NMR (400 MHz, CDCl ) δ 7.36 – 7.31 (m, 2H), 7.30 – 7.27 (m, 3H), 7.13 (t,
3
J = 2.3 Hz, 1H), 6.82 (dt, J = 8.6, 2.1 Hz, 1H), 6.64 (dd, J = 8.6, 1.3 Hz, 1H), 4.95 (d, J = 15.7
1
3
1
Hz, 1H), 4.83 (d, J = 15.7 Hz, 1H), 4.20 – 4.07 (m, 2H), 3.78 (s, 3H), 2.35 (br. s, 1H). C{ H}
NMR (100 MHz, CDCl ) δ 171.7 (d, J = 20 Hz), 156.4 (d, JC-F = 3 Hz), 136.6 (d, JC-F = 5
3
C-F
Hz), 134.9, 128.9, 127.9, 127.2, 125.0 (d, JC-F = 19 Hz), 116.0 (d, JC-F = 3 Hz), 112.4, 110.6,
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1.8 (d, JC-F = 190 Hz), 64.6 (d, JC-F = 31 Hz), 55.9, 43.9. F NMR (CDCl , 376 MHz): δ -
3
+
169.3. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H FNO Na324.1006; found 324.0983.
1
7
16
3
1
-Benzyl-5-chloro-3-fluoro-3-(hydroxymethyl)indolin-2-one (2k): The compound was
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prepared by following general procedure and was obtained as white solid (0.081 g, 76%), mp
1
171−172 °C. H NMR (400 MHz, CDCl ): δ 7.53 (t, J = 2.0 Hz, 1H), 7.42 – 7.22 (m, 6H), 6.66
3
(
dd, J = 8.4, 1.3 Hz, 1H), 4.96 (d, J = 15.8 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.27 – 4.00 (m,
1
3
1
2
H), 2.25 (dd, J = 8.5, 4.5 Hz, 1H). C{ H} NMR (100 MHz, CDCl ): δ 171.4 (d, J = 20.4
3 C-F
Hz), 141.9 (d, JC-F = 4.9 Hz), 134.3, 131.3 (d, JC-F = 2.8 Hz), 129.0, 128.9, 128.1, 127.1, 126.1,
1
9
125.6 (d, JC-F = 18.4 Hz), 111.0, 91.4 (d, JC-F = 190.0 Hz), 64.2 (d, JC-F = 30.9 Hz), 44.0. F
+
NMR (CDCl , 376 MHz): δ -169.2. HRMS (ESI-TOF) m/z: [M+Na] Calcd for
3
C H ClFNO Na 328.0511; found 328.0508.
1
6
13
2
1
-Benzyl-5-bromo-3-fluoro-3-(hydroxymethyl)indolin-2-one (2l): The compound was
prepared by following general procedure and was obtained as white solid (0.09 g, 82%), mp
1
1
59−160 °C. H NMR (400 MHz, CDCl ) δ 7.66 (t, J = 2.0 Hz, 1H), 7.42 (dt, J = 8.3, 1.8 Hz,
3
1H), 7.36 – 7.25 (m, 5H), 6.61 (dd, J = 8.3, 1.3 Hz, 1H), 4.96 (d, J = 15.8 Hz, 1H), 4.84 (d, J
1
3
1
=
15.8 Hz, 1H), 4.25 – 4.04 (m, 2H), 2.25 (d, J = 5.0 Hz, 1H). C{ H} NMR (100 MHz,
CDCl ) δ 171.3 (d, J = 20 Hz), 142.5 (d, JC-F = 5 Hz), 134.3, 134.2 (d, JC-F = 3 Hz), 129.0,
3
C-F
1
28.8, 128.1, 127.1, 125.9 (d, JC-F = 19 Hz), 116.1 (d, JC-F = 3 Hz), 111.4, 91.4 (d, JC-F = 190
1
9
Hz), 64.2 (d, JC-F = 31 Hz), 43.9. F NMR (CDCl , 376 MHz): δ -169.1. HRMS (ESI-TOF)
3
+
m/z: [M+Na] Calcd for C H BrFNO Na 372.0006; found 371.9989.
1
6
13
2
1-Benzyl-3,5-difluoro-3-(hydroxymethyl)indolin-2-one (2m): The compound was prepared
by following general procedure and was obtained as white solid (0.084 g, 77%), mp 161−163
1
°
C. H NMR (400 MHz, CDCl ) δ 7.40 – 7.23 (m, 6H), 7.00 (tdd, J = 8.8, 2.6, 1.7 Hz, 1H),
3
6
.66 (ddd, J = 8.6, 4.0, 1.3 Hz, 1H), 4.97 (d, J = 15.8 Hz, 1H), 4.85 (d, J = 15.8 Hz, 1H), 4.21
(ddd, J = 14.2, 12.2, 4.3 Hz, 1H), 4.09 (ddd, J = 18.6, 12.3, 8.6 Hz, 1H), 2.31 (dd, J = 8.7, 4.4
1
3
1
Hz, 1H). C{ H} NMR (100 MHz, CDCl ) δ 171.6 (d, J = 21 Hz), 160.5 (d, JC-F = 3 Hz),
3
C-F
1
58.1 (d, JC-F = 3 Hz), 139.2 (q, JC-F = 5 Hz), 134.5, 129.0, 128.0, 127.1, 125.5 (q, JC-F = 19
Hz), 117.8 (d, JC-F = 3 Hz), 117.6 (d, JC-F = 3 Hz), 113.8 (d, JC-F = 26 Hz), 110.7 (d, JC-F = 8
1
9
Hz), 91.6 (dd, JC-F = 190, 1.6 Hz), 64.3 (d, JC-F = 30 Hz), 44.0. F NMR (CDCl , 376 MHz):
3
+
δ -118.7, -169.4. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H F NO Na312.0807; found
1
6
13
2
2
3
12.0781.
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1-Benzyl-3-fluoro-3-(hydroxymethyl)-5-iodoindolin-2-one (2n): The compound was
prepared by following general procedure and was obtained as white solid (0.085 g, 79%), mp
1
1
58−160 °C. H NMR (400 MHz, CDCl ) δ 7.82 (t, J = 1.8 Hz, 1H), 7.61 (dt, J = 8.3, 1.8 Hz,
3
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H), 7.38 – 7.21 (m, 5H), 6.51 (dd, J = 8.3, 1.3 Hz, 1H), 4.95 (d, J = 15.8 Hz, 1H), 4.83 (d, J
1
3
1
= 15.8 Hz, 1H), 4.30 – 3.94 (m, 2H), 2.42 (br. s, 1H). C{ H} NMR (100 MHz, CDCl ) δ
3
1
1
71.1 (d, JC-F = 20 Hz), 143.1 (d, JC-F = 5 Hz), 140.2 (d, JC-F = 3 Hz), 134.3 (d, JC-F = 3 Hz),
29.0, 128.0, 127.1, 126.2 (d, JC-F = 19 Hz), 111.9, 91.2 (d, JC-F = 190 Hz), 85.9 (d, JC-F = 3
1
9
Hz), 64.2 (d, JC-F = 31 Hz), 43.9. F NMR (CDCl , 376 MHz): δ -169.0. HRMS (ESI-TOF)
3
+
m/z: [M+Na] Calcd for C H FINO Na 419.9867; found 419.9850.
1
6
13
2
3
-Fluoro-3-(hydroxymethyl)indolin-2-one (2o): The compound was prepared by following
1
general procedure and was obtained as colourless gummy liquid (0.070 g, 62%). H NMR (400
MHz, DMSO-d ): δ 10.62 (s, 1H), 7.48 (dt, J = 7.4, 1.6 Hz, 1H), 7.34 (tt, J = 7.8, 1.7 Hz, 1H),
6
7
1
.04 (tt, J = 7.5, 1.0 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.38 (t, J = 5.7 Hz, 1H), 3.94 (ddd, J =
13
1
1.2, 8.8, 5.0 Hz, 1H), 3.75 (ddd, J = 17.8, 11.2, 6.2 Hz, 1H). C{ H} NMR (100 MHz,
DMSO-d ): δ 172.9 (d, J = 19.4 Hz), 143.2 (d, JC-F = 5.8 Hz), 131.2 (d, JC-F = 3.2 Hz), 125.9,
6
C-F
1
24.9 (d, JC-F =18.2 Hz), 122.1 (d, JC-F = 2.8 Hz), 110.2, 92.6 (d, JC-F = 184.1 Hz), 62.1 (d, JC-
19
+
=
33.2 Hz). F NMR (CDCl , 376 MHz): δ -164.8. HRMS (ESI-TOF) m/z: [M+Na] Calcd
3
F
for C H FNO Na 204.0431; found 204.0425.
9
8
2
3
-fluoro-3-(hydroxymethyl)-1-tosylindolin-2-one (2p): The compound was prepared by
following general procedure and was obtained as white solid (0.068 g, 66%) mp 117−119 °C.
1
H NMR (400 MHz, CDCl ) δ 8.04 – 7.90 (m, 3H), 7.51 (td, J = 7.4, 1.7 Hz, 2H), 7.35 (d, J =
3
1
3
1
8
.1 Hz, 2H), 7.30 – 7.23 (m, 1H), 4.09 – 3.96 (m, 2H), 2.44 (s, 3H), 1.96 (br. s, 1H). C{ H}
NMR (100 MHz, CDCl ) δ 170.1(d, J = 21 Hz), 146.2, 140.0 (d, JC-F = 5 Hz), 134.5, 132.3,
3
C-F
1
30.0, 128.0, 125.7, 125.5 (d, JC-F = 2 Hz), 123.1 (d, JC-F = 19 Hz), 114.1, 91.2 (d, JC-F = 192
1
9
Hz), 64.4 (d, JC-F = 32 Hz), 21.8. F NMR (CDCl , 376 MHz): δ -163.9. HRMS (ESI-TOF)
3
+
m/z: [M+Na] Calcd for C H FNO SNa 358.0520; found 358.0523.
1
6
14
4
General procedure for ring-opening reaction Spiro-epoxyoxindoles with TBAF: To a
stirring solution of spiro-epoxy oxindole 1a (0.100 g, 0.570 mmol) in dry DMF (4 mL), TBAF
(1M in THF) (1.71 mL, 1.712 mmol) was added and the reaction mixture was allowed to heat
at 50 °C at oil bath. The resulting solution was stirred at the same temperature and monitored
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by TLC. On completion (6 h), the reaction was diluted with water, extracted with EtOAc (3×5
mL), washed with brine solution and dried over anhydrous Na SO . Combined organic layers
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4
were concentrated and purified by silicagel flash chromatography using EtOAc/hexane (1:4)
to afford the desired product 3a (0.069 g, 62%).
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3-(Fluoromethyl)-3-hydroxy-1-methylindolin-2-one (3a): The compound was prepared by
following general procedure and was obtained as white solid (0.072 g, 63%), mp 143−145 °C.
1
H NMR (400 MHz, CDCl ) δ 7.49 – 7.44 (m, 1H), 7.40 (td, J = 7.8, 1.3 Hz, 1H), 7.15 (td, J
3
=
7.6, 1.0 Hz, 1H), 6.89 (dt, J = 7.8, 0.7 Hz, 1H), 4.67 (br. s, 1H), 4.55 (d, J = 0.9 Hz, 1H),
1
3
1
3.48 – 3.34 (m, 1H), 3.23 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 175.5 (d, J = 3.5 Hz),
3
C-F
1
43.8, 130.6, 126.6 (d, JC-F = 2 Hz), 124.6, 123.4, 108.7, 84.7 (d, JC-F = 179 Hz), 74.9 (d, JC-F
19
+
=
20 Hz), 26.4. F NMR (CDCl , 376 MHz): δ -229.9. HRMS (ESI-TOF) m/z: [M+Na]
3
Calcd for C H FNO Na 218.0588; found 218.0602.
10
10
2
1
-Benzyl-3-(fluoromethyl)-3-hydroxyindolin-2-one (3b): The compound was prepared by
1
following general procedure and was obtained as yellow gummy liquid (0.061 g, 59%). H
NMR (400 MHz, CDCl ) δ 7.47 (dd, J = 7.4, 1.3 Hz, 1H), 7.35 – 7.24 (m, 6H), 7.13 – 7.08 (m,
3
1
H), 6.74 (d, J = 7.9 Hz, 1H), 5.03 (d, J = 15.8 Hz, 1H), 4.84 – 4.69 (m, 2H), 4.62 (q, J = 9.2
13
1
Hz, 1H), 3.65 (br. s, 1H). C{ H} NMR (100 MHz, CDCl ) δ 175.7 (d, J = 3 Hz), 143.0,
3
C-F
1
35.0, 130.5, 128.9, 127.8, 127.1, 126.7, 124.6, 123.5, 109.8, 84.7 (d, JC-F = 180 Hz), 74.9 (d,
1
9
+
JC-F = 21 Hz), 43.9. F NMR (CDCl , 376 MHz): δ -229.1. HRMS (ESI-TOF) m/z: [M+Na]
3
Calcd for C H FNO Na 294.0901; found 294.0903.
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14
2
1-Allyl-3-(fluoromethyl)-3-hydroxyindolin-2-one (3c): The compound was prepared by
following general procedure and was obtained as orange solid (0.075 g, 66%), mp 93−94 °C.
1
H NMR (400 MHz, CDCl ) δ 7.47 (dd, J = 7.2, 1.2 Hz, 1H), 7.36 (td, J = 7.8, 1.3 Hz, 1H),
3
7
.14 (td, J = 7.6, 1.0 Hz, 1H), 6.87 (dt, J = 7.9, 0.7 Hz, 1H), 5.84 (ddt, J = 17.3, 10.3, 5.2 Hz,
1H), 5.31 – 5.16 (m, 2H), 4.75 – 4.64 (m, 1H), 4.63 – 4.52 (m, 1H), 4.42 (ddt, J = 16.5, 5.2,
1
3
1
1
.8 Hz, 1H), 4.26 (ddt, J = 16.4, 5.2, 1.7 Hz, 1H), 3.48 (s, 1H). C{ H} NMR (100 MHz,
CDCl ) δ 175.3 (d, J = 3 Hz), 143.1, 130.5 (d, JC-F = 12 Hz), 126.7 (d, JC-F = 2 Hz), 124.7,
3
C-F
1
9
123.4, 117.8, 109.7, 84.7 (d, JC-F = 180 Hz), 74.8 (d, JC-F = 21 Hz), 42.4. F NMR (CDCl ,
3
+
3
76 MHz): δ -229.3. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H FNO Na 244.0744;
12 12
2
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-(Fluoromethyl)-3-hydroxy-1-(4-methoxybenzyl)indolin-2-one (3d): The compound was
prepared by following general procedure and was obtained as yellow gummy liquid (0.08 g,
1
7
1
7
0%). H NMR (400 MHz, CDCl ) δ 7.46 (dd, J = 7.4, 1.3 Hz, 1H), 7.27 (td, J = 8.0, 1.3 Hz,
3
H), 7.24 – 7.18 (m, 2H), 7.10 (td, J = 7.6, 1.0 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 6.77 (d, J =
.8 Hz, 1H), 4.95 (d, J = 15.5 Hz, 1H), 4.78 – 4.68 (m, 2H), 4.61 (q, J = 9.2 Hz, 1H), 3.77 (s,
1
1
1
1
1
1
1
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2
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2
2
2
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7
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9
0
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1
3
1
3H). C{ H} NMR (100 MHz, CDCl ) δ 175.7 (d, J = 3 Hz), 159.2, 143.0, 130.4, 128.5,
3
C-F
1
4
27.0, 126.8, 124.6, 123.4, 114.3, 109.9, 84.7 (d, JC-F = 180 Hz), 74.9 (d, JC-F = 21 Hz), 55.2,
1
9
+
3.4. F NMR (CDCl , 376 MHz): δ -229.2. HRMS (ESI-TOF) m/z: [M+Na] Calcd for
3
C H FNO Na 324.1006; found 324.1025.
1
7
16
3
3-(Fluoromethyl)-3-hydroxy-1,5-dimethylindolin-2-one (3e): The compound was prepared
by following general procedure and was obtained as red solid (0.079 g, 65%), mp 118−120 °C.
1
H NMR (400 MHz, CDCl ) δ 7.28 (br. S, 1H), 7.19 (ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 6.77 (d, J
3
= 7.9 Hz, 1H), 4.66 (d, J = 1.3 Hz, 1H), 4.54 (d, J = 1.6 Hz, 1H), 3.68 (s, 1H), 3.25 – 3.15 (m,
1
3
1
3
1
2
H), 2.36 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 175.5 (d, J = 3 Hz), 141.4, 133.1,
3 C-F
30.7, 126.6 (d, JC-F = 2 Hz), 125.4, 108.5, 84.7 (d, JC-F = 179 Hz), 75.0 (d, JC-F = 20 Hz), 26.4,
19
+
1.0. F NMR (CDCl , 376 MHz): δ -229.8. HRMS (ESI-TOF) m/z: [M+Na] Calcd for
3
C H FNO Na 232.0744; found 232.0752.
1
1
12
2
3
-(Fluoromethyl)-3-hydroxy-1,5,7-trimethylindolin-2-one (3f): The compound was
prepared by following general procedure and was obtained as orange solid (0.073 g, 66%), mp
1
1
54−155 °C. H NMR (400 MHz, CDCl ): δ 7.10 (s, 1H), 6.92 (s, 1H), 4.62 (q, J = 9.2 Hz,
3
1
3
1
1
H), 4.54 – 4.45 (m, 1H), 3.46 (s, 3H), 3.35 (s, 1H), 2.53 (s, 3H), 2.30 (3H). C{ H} NMR
(100 MHz, CDCl ): δ 176.1 (d, J = 2.9 Hz), 139.0, 134.7, 133.0, 127.3 (d, JC-F = 1.7 Hz),
3 C-F
1
9
123.2, 120.2, 84.9 (d, JC-F = 179.6 Hz), 74.2 (d, JC-F = 20.6 Hz), 29.7, 20.7, 18.7. F NMR
+
(CDCl , 376 MHz): δ -229.3. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H FNO Na
3
12 14
2
2
46.0901; found 246.0913.
5-Chloro-3-(fluoromethyl)-3-hydroxy-1-methylindolin-2-one (3g): The compound was
prepared by following general procedure and was obtained as yellow solid (0.067 g, 59%), mp
1
1
32−134 °C. H NMR (400 MHz, CDCl ) δ 7.45 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.3, 2.2 Hz,
3
1
3
1
1H), 6.82 (d, J = 8.3 Hz, 1H), 4.66 (s, 1H), 4.54 (s, 1H), 3.21 (s, 3H). C{ H} NMR (100
MHz, CDCl ) δ 175.1 (d, J
=
3
C-F
= 4 Hz)142.3, 130.4, 129.0, 128.4, 125.3, 109.8, 84.5 (d, JC-F
1
9
1
80 Hz), 74.9 (d, JC-F = 21 Hz), 26.6. F NMR (CDCl , 376 MHz): δ -230.1. HRMS (ESI-
3
+
TOF) m/z: [M+Na] Calcd for C H ClFNO Na 252.0198; found 252.0177.
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prepared by following general procedure and was obtained as yellow solid (0.064 g, 62%), mp
1
1
79−181 °C. H NMR (400 MHz, CDCl ) δ 7.83 – 7.65 (m, 2H), 6.67 (d, J = 8.1 Hz, 1H), 4.64
3
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1
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3
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0
13
1
(
s, 1H), 4.53 (s, 1H), 3.34 (s, 1H), 3.20 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 174.8 (d,
3
JC-F = 3 Hz), 143.5, 139.3, 133.6, 129.0, 110.8, 85.9, 84.5 (d, JC-F = 180 Hz),, 74.7 (d, JC-F
=
1
9
+
2
1 Hz), 26.5. F NMR (CDCl , 376 MHz): δ -229.9. HRMS (ESI-TOF) m/z: [M+Na] Calcd
3
for C H FINO Na 343.9554; found 343.9570.
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0
9
2
7-Chloro-3-(fluoromethyl)-3-hydroxy-1-methylindolin-2-one (3i): The compound was
prepared by following general procedure and was obtained as yellow solid (0.064 g, 60%), mp
1
1
15−117 °C. H NMR (400 MHz, CDCl ) δ 7.34 (ddd, J = 15.2, 7.8, 1.1 Hz, 2H), 7.06 (dd, J
3
1
3
1
= 8.2, 7.4 Hz, 1H), 4.69 – 4.58 (m, 1H), 4.58 – 4.47 (m, 1H), 3.67 (s, 1H), 3.58 (s, 3H). C{ H}
NMR (100 MHz, CDCl ) δ 175.9 (d, J = 3 Hz), 139.7, 132.8, 129.6, 124.3, 123.2, 116.2,
3
C-F
1
9
8
4.6 (d, JC-F = 180 Hz), 74.3 (d, JC-F = 21 Hz), 29.9. F NMR (CDCl , 376 MHz): δ -229.7.
3
+
HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H ClFNO Na 252.0198; found 252.0200.
1
0
9
2
1
-Benzyl-3-(fluoromethyl)-3-hydroxy-5,7-dimethylindolin-2-one (3j): The compound was
prepared by following general procedure and was obtained as yellow gummy liquid (0.061 g,
1
5
5%). H NMR (400 MHz, CDCl ) δ 7.34 – 7.22 (m, 3H), 7.19 – 7.11 (m, 3H), 6.89 – 6.81
3
(m, 1H), 5.23 (d, J = 16.8 Hz, 1H), 5.09 (d, J = 16.9 Hz, 1H), 4.67 (ddd, J = 47.0, 33.5, 9.0 Hz,
1
3
1
2
H), 3.65 (s, 1H), 2.30 (s, 3H), 2.20 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 176.8 (d, J
3 C-F
=
2 Hz), 138.5, 136.8, 134.9, 133.3, 128.9, 127.5, 127.3, 125.5, 123.2, 120.3, 84.9 (d, JC-F =
1
9
179 Hz), 74.1 (d, JC-F = 21 Hz), 45.1, 20.7, 18.5. F NMR (CDCl , 376 MHz): δ -228.3.
3
+
HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H FNO Na 322.1214; found 322.1223.
18 18
2
1
-Benzyl-5-bromo-3-(fluoromethyl)-3-hydroxyindolin-2-one (3k): The compound was
prepared by following general procedure and was obtained as red gummy liquid (0.062 g,
1
5
7
8%). H NMR (400 MHz, CDCl ) δ 7.59 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.3, 2.0 Hz, 1H),
3
.36 – 7.21 (m, 5H), 6.60 (d, J = 8.4 Hz, 1H), 5.01 (d, J = 15.8 Hz, 1H), 4.83 – 4.67 (m, 2H),
1
3
1
4.65 – 4.55 (m, 1H), 3.54 (s, 1H). C{ H} NMR (100 MHz, CDCl ) δ 175.2 (d, J = 3 Hz),
3
C-F
1
7
42.0, 134.4, 133.3, 129.0, 128.7, 128.1, 128.0, 127.0, 116.2, 111.4, 85.5 (d, JC-F = 180 Hz),
1
9
4.8 (d, JC-F = 21 Hz), 44.1. F NMR (CDCl , 376 MHz): δ -229.2. HRMS (ESI-TOF) m/z:
3
+
[
M+Na] Calcd for C H BrFNO Na 372.0006; found 372.0009.
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1-Benzyl-5-fluoro-3-(fluoromethyl)-3-hydroxyindolin-2-one (3l): The compound was
prepared by following general procedure and was obtained as yellow gummy liquid (0.064 g,
1
5
7%). H NMR (400 MHz, CDCl ) δ 7.37 – 7.17 (m, 6H), 6.94 (td, J = 8.8, 2.6 Hz, 1H), 6.63
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
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4
5
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7
8
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0
1
2
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7
8
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0
1
2
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7
8
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0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(dd, J = 8.6, 4.0 Hz, 1H), 5.01 (d, J = 15.8 Hz, 1H), 4.81 – 4.68 (m, 2H), 4.65 – 4.56 (m, 1H),
1
3
1
4.05 (s, 1H). C{ H} NMR (100 MHz, CDCl ) δ 175.8 (d, J = 3 Hz), 159.6 (d, JC-F = 242
3
C-F
Hz), 138.7 (d, JC-F = 2 Hz), 134.6, 128.9, 128.6 (d, JC-F = 8 Hz), 127.9, 127.0, 116.7 (d, JC-F
=
=
2
3 Hz), 113.0 (d, JC-F = 25 Hz), 110.6 (d, JC-F = 8 Hz), 84.6 (d, JC-F = 180 Hz), 75.2 (dd, JC-F
1
9
2
1, 2 Hz), 44.1. F NMR (CDCl , 376 MHz): δ -118.9, -229.4. HRMS (ESI-TOF) m/z:
3
+
[M+Na] Calcd for C H F NO Na 312.0807; found 312.0812.
1
6
13
2
2
1
-Benzyl-3-(fluoromethyl)-3-hydroxy-5-iodoindolin-2-one (3m): The compound was
prepared by following general procedure and was obtained as yellow gummy liquid (0.063 g,
1
5
7
4
8%). H NMR (400 MHz, CDCl ) δ 7.67 (d, J = 1.7 Hz, 1H), 7.50 (dd, J = 8.3, 1.8 Hz, 1H),
3
.27 – 7.21 (m, 2H), 7.20 – 7.15 (m, 3H), 6.42 (d, J = 8.3 Hz, 1H), 4.91 (d, J = 15.8 Hz, 1H),
13
1
.70 (d, J = 15.8 Hz, 1H), 4.67 – 4.58 (m, 1H), 4.55 – 4.47 (m, 1H), 3.24 (br. s, 1H). C{ H}
NMR (100 MHz, CDCl ) δ 174.9 (d, J = 3 Hz), 142.7, 139.3, 134.5, 133.6, 129.0, 128.0,
3
C-F
1
9
1
27.0, 111.89, 86.0, 84.5 (d, JC-F = 180 Hz), 74.6 (d, JC-F = 21 Hz), 44.0. F NMR (CDCl ,
3
+
3
76 MHz): δ -229.2. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C H FINO Na 419.9867;
1
6
13
2
found 419.9860.
1
-Benzyl-3-(bromomethyl)-3-fluoroindolin-2-one (5): To a stirring solution of compound 2b
(0.100 g, 0.368 mmol) in dry 1,2-dichloroethane (5 mL), triphenyl phosphine (0.580 g, 2.21
mmol) and carbon tetrabromide (0.732 g, 2.21 mmol) were added sequentially at 0 °C and the
resulting solution was heated at 50 °C at oil bath for 4 h. Solvent was evaporated and purified
by silicagel flash chromatography using 8% EtOAc/hexane to afford the desire product 5 (
1
0
.117 g, 95%) as colourless liquid. H NMR (400 MHz, Chloroform-d) δ 7.57 (dt, J = 7.4, 1.7
Hz, 1H), 7.40 – 7.21 (m, 6H), 7.13 (tt, J = 7.6, 1.0 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 5.06 (d, J
1
3
1
=
15.8 Hz, 1H), 4.81 (d, J = 15.7 Hz, 1H), 4.17 – 3.82 (m, 2H). C{ H} NMR (100 MHz,
CDCl ) δ 170.6 (d, J = 21 Hz), 143.8 (d, JC-F = 5 Hz), 134.7, 131.9 (d, JC-F = 3 Hz), 128.9,
3
C-F
127.9, 127.2, 127.1, 125.1, 123.7 (d, JC-F = 19 Hz), 123.4 (d, JC-F = 3 Hz), 110.0, 90.6 (d, JC-F
1
9
=
189 Hz), 44.1, 30.1 (d, JC-F = 36 Hz). F NMR (CDCl , 376 MHz): δ -150.2. HRMS (ESI-
3
+
TOF) m/z: [M+Na] Calcd for C H BrFNONa 356.0057; found 356.0080.
1
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5
5
6
(
1-Benzyl-3-fluoro-2-oxoindolin-3-yl)methyl 4-methylbenzenesulfonate (6): To a stirring
solution of Compound 2b (0.100 g, 0.368 mmol) in dry dichloromethane (4 mL) at 0°C
immersion bath), triethyl amine (0.102 mL, 0.737 mmol) and tosyl chloride ( 0.106 g, 0.552
(
mmol) were added sequentially. Then the resulting solution was stirred at 25°C and monitored
by TLC. On completion, solvent was evaporated and the residue was purified by silicagel flash
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
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4
5
6
7
8
9
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1
2
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4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
chromatography using EtOAc/hexane (1:9) to afford the desire product 6 (0.15 g, 95%) as
1
gummy liquid. H NMR (400 MHz, CDCl ) δ 7.75 – 7.66 (m, 2H), 7.48 (dt, J = 7.5, 1.7 Hz,
3
1
H), 7.35 – 7.24 (m, 8H), 7.08 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 4.97 (d, J = 15.8
Hz, 1H), 4.78 (d, J = 15.8 Hz, 1H), 4.60 (dd, J = 10.3, 8.1 Hz, 1H), 4.37 (dd, J = 18.8, 10.3 Hz,
1
3
1
1H), 2.46 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 169.8 (d, J = 20 Hz), 145.3, 143.4
3
C-F
(d, JC-F = 5 Hz), 134.5, 131.9 (d, JC-F = 4 Hz), 130.0, 129.0, 128.0, 127.9, 127.0, 126.2, 123.6,
22.5 (d, JC-F = 20 Hz), 110.0, 89.5 (d, JC-F = 191 Hz), 68.6 (d, JC-F = 36 Hz), 44.0, 21.7. 19F
1
+
NMR (CDCl , 376 MHz): δ -165.2. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H FNO S
3
23 21
4
4
26.1170; found 426.1142.
3
-(Azidomethyl)-1-benzyl-3-fluoroindolin-2-one (7): Compound 6 (0.05 g, 0.117 mmol) was
dissolved in dry DMF (2 mL) at 25°C. Sodium azide (0.038 g, 0.038 mmol) was added to the
mixture and the resulting mixture was heated 100°C for 14 h. On completion cold water was
added, extracted with EtOAc (3×5 mL), washed with brine solution and dried over anhydrous
Na SO . Combined organic layers were concentrated and purified by silicagel flash
2
4
chromatography using EtOAc/hexane (1:10) to afford the desire product 7 (0.031 g, 90%) as
1
colorless gummy liquid. H NMR (400 MHz, CDCl ) δ 7.58 (dt, J = 7.4, 1.6 Hz, 1H), 7.44 –
3
7
.20 (m, 6H), 7.17 – 7.07 (m, 1H), 6.83 – 6.69 (m, 1H), 5.00 (d, J = 15.7 Hz, 1H), 4.84 (d, J =
1
3
1
15.7 Hz, 1H), 4.09 (dd, J = 12.7, 8.8 Hz, 1H), 3.72 (dd, J = 18.7, 12.7 Hz, 1H). C{ H} NMR
100 MHz, CDCl ) δ 170.9 (d, J
(
= 20 Hz), 143.4 (d, JC-F = 5 Hz), 134.7, 131.8 (d, JC-F = 3
C-F
3
Hz), 129.0, 128.0, 127.2, 125.7, 123.6, 123.5 (d, JC-F = 3 Hz), 110.0, 90.9 (d, JC-F = 191 Hz),
19
5
3.7 (d, JC-F = 33 Hz), 44.0. F NMR (CDCl , 376 MHz): δ -162.1. HRMS (ESI-TOF) m/z:
3
+
[M+Na] Calcd for C H FN ONa 319.0966; found 319.0960.
1
6
13
4
1
-Benzyl-3-methylindolin-2-one (8): To a stirring solution of compound 6 (0.08 g, 0.188
mmol) in dry THF (2 mL) at 0°C (immersion bath), Super hydride (1M in THF) (0.94 mL, 0.94
mmol) was added. Then the resulting solution was allowed to warm at 25°C and monitored by
TLC. On completion (2 h), the reaction was quenched with saturated aqueous solution of
NH Cl, extracted with EtOAc (3×5 mL), washed with brine solution and dried over anhydrous
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Na SO . Combined organic layers were concentrated and purified by silicagel flash
2
4
chromatography using EtOAc/hexane (1:4) to afford the desire product 8 (0.042 g, 95%) as
1
white solid, mp 115−116 °C. H NMR (400 MHz, CDCl ): δ 7.35 – 7.22 (m, 6H), 7.17 (tt, J =
3
7
.8, 1.0 Hz, 1H), 7.03 (td, J = 7.6, 0.9 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.92 (s, 2H), 3.55 (q,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
J = 7.6 Hz, 1H), 1.55 (d, J = 7.6 Hz, 3H). C{ H} NMR (100 MHz, CDCl ): δ 178.7, 143.0,
3
135.9, 130.6, 128.7, 127.8, 127.5, 127.2, 123.5, 122.4, 108.9, 43.6, 40.5, 15.6. HRMS (ESI-
+
TOF) m/z: [M+Na] Calcd for C H NONa 260.1046; found 260.1063.
1
6
15
3
-(Fluoromethyl)-3-(4-methoxyphenyl)-1-methylindolin-2-one (10): To a stirring solution
of compound 3a (0.100 g, 0.512 mmol) in dry dichloromethane (2.5 mL) at 0 °C (immersion
bath), DBU (0.09 mL, 0.614 mmol) and trichloroacetonitrile (0.1 mL, 0.768 mmol) were added
sequential. Then the resulting solution was stirred at 25 °C and monitored by TLC. On
completion, the reaction was quenched with saturated aqueous solution of NH Cl, extracted
4
with EtOAc (3×5 mL), washed with brine solution and dried over anhydrous Na SO .
2
4
Combined organic layers were concentrated. The residue was dissolved in dry 1,2-
dichloroethane (2 mL). Anisole (0.24 g, 0.22 mmol) and BF .OEt (.003 mL, 0.029 mmol)
3
2
were added sequential. The resulting solution was stirred at 25 °C. On completion (2 h), the
reaction was quenched with saturated aqueous solution of NaHCO , extracted with EtOAc (3×5
3
mL), washed with brine solution and dried over anhydrous Na SO . Combined organic layers
2
4
were concentrated and purified by silicagel flash chromatography using EtOAc/hexane (1:9)
1
to afford the desire product 10 (0.131 g, 90%) as yellow solid, mp 116−117 °C. H NMR (400
MHz, ) δ 7.41 (dd, J = 7.8, 1.3 Hz, 2H), 7.37 – 7.34 (m, 2H), 7.22 – 7.15 (m, 1H), 6.94 (dt, J =
13
1
7
.6, 0.9 Hz, 1H), 6.91 – 6.81 (m, 2H), 5.10 – 4.83 (m, 2H), 3.78 (s, 3H), 3.23 (s, 3H). C{ H}
NMR (100 MHz, CDCl ) δ 175.8 (d, J = 4 Hz), 159.3, 144.1, 129.0, 128.9, 128.3, 127.1 (d,
3
C-F
JC-F = 6 Hz), 125.4, 122.8, 114.2, 108.6, 85.7 (d, JC-F = 179 Hz), 56.7 (d, JC-F = 20 Hz), 55.3,
1
9
+
2
6.6. F NMR (CDCl , 376 MHz): δ -221.2. HRMS (ESI-TOF) m/z: [M+H] Calcd for
3
C H FNO 286.1238; found 286.1237.
1
7
17
2
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*saumen.hajra@cbmr.res.in
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Fax: (+91)-522-2668995; Tel.: (+91)-522-2668861
Notes
The authors declare no competing financial interest
Supporting Information
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NMR spectra for all new compounds 2, 3, 5, 6, 7, 8, 10. This material is available free of charge
via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We thank SERB, New Delhi (EMR/2016/001161) for providing financial support. S.R. and
S.M thank CSIR, New Delhi, respectively, for their fellowships. We thank the Director of
CBMR for providing research facilities.
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